Impact of Chk1 dosage on somatic hypermutation in vivo

Immunol Cell Biol. 2021 Sep;99(8):879-893. doi: 10.1111/imcb.12480. Epub 2021 Jun 19.


Checkpoint signaling in the context of a functional DNA damage response is crucial for the prevention of oncogenic transformation of cells. Our immune system, though, takes the risk of attenuated checkpoint responses during immunoglobulin diversification. B cells undergo continuous DNA damage and error-prone repair of their immunoglobulin genes during the process of somatic hypermutation. An accompanying attenuation of the DNA damage response via the ATR-Chk1 axis in B cells is believed to allow for a better DNA damage tolerance and for evasion of apoptosis, so as to ensure mutations to be passed on. We sought to determine whether the downregulation of Chk1 could also directly influence the process of hypermutation in vivo by altering the relative activity of error-prone DNA repair pathways. We analyzed the humoral response and the hypermutation process in mice whose B cells express reduced levels of the Chk1 protein. We found that Chk1 heterozygosity limits the accumulation of mutations in the immunoglobulin loci, likely by impacting on the survival of B cells as they accumulate DNA damage. Nevertheless, we unveiled an unanticipated role for Chk1 downregulation in favoring A/T mutagenesis at the antibody-variable regions during hypermutation. Even though immunoglobulin mutagenesis was found to be reduced, Chk1 signaling attenuation allows for sustained mutagenesis outside the immunoglobulin loci. Our study thus reveals that a proper Chk1 dosage is crucial for adequate somatic hypermutation in B cells.

Keywords: checkpoint kinase 1; class switch recombination; germinal center; noncanonical mismatch repair; somatic hypermutation.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • B-Lymphocytes*
  • DNA Damage / genetics
  • Immunoglobulin Variable Region
  • Mice
  • Mutagenesis
  • Somatic Hypermutation, Immunoglobulin* / genetics


  • Immunoglobulin Variable Region